Whole-genome DNA methylation characteristics in pediatric precursor B cell acute lymphoblastic leukemia (BCP ALL)

<div><p>In addition to genetic alterations, epigenetic abnormalities have been shown to underlie the pathogenesis of acute lymphoblastic leukemia (ALL)—the most common pediatric cancer. The purpose of this study was to characterize the whole genome DNA methylation profile in children with precursor B-cell ALL (BCP ALL) and to compare this profile with methylation observed in normal bone marrow samples. Additional efforts were made to correlate the observed methylation patterns with selected clinical features. We assessed DNA methylation from bone marrow samples obtained from 38 children with BCP ALL at the time of diagnosis along with 4 samples of normal bone marrow cells as controls using Infinium MethylationEPIC BeadChip Array. Patients were diagnosed and stratified into prognosis groups according to the BFM ALL IC 2009 protocol. The analysis of differentially methylated sites across the genome as well as promoter methylation profiles allowed clear separation of the leukemic and control samples into two clusters. 86.6% of the promoter-associated differentially methylated sites were hypermethylated in BCP ALL. Seven sites were found to correlate with the BFM ALL IC 2009 high risk group. Amongst these, one was located within the gene body of the <i>MBP</i> gene and another was within the promoter region- <i>PSMF1</i> gene. Differentially methylated sites that were significantly related with subsets of patients with <i>ETV6-RUNX1</i> fusion and hyperdiploidy. The analyzed translocations and change of genes’ sequence context does not affect methylation and methylation seems not to be a mechanism for the regulation of expression of the resulting fusion genes.</p></div

Unsupervised hierarchical clustering of promoter regions-associated methylation profiles in leukemic and control samples.

<p>Unsupervised hierarchical clustering of promoter regions-associated methylation profiles in leukemic and control samples.</p

Principal component analysis 3D plot based on 500 probes with the highest differences in methylation level among genetic subtypes and remaining pre-B ALL patients.

<p>The plot is presented in three different layouts to enable visualization of separate clusters.</p

The characteristics of patients.

<p>The characteristics of patients.</p

Methylation profile of <i>TCF3</i> and <i>PBX1</i> genes in <i>TCF3-PBX1</i> subtype patients, remaining pre-B ALL cases and control individuals.

<p>Red square marks the CpG fragments with large differences in methylation level between pre-B ALL and control samples.</p

Distribution of hyper- and hypomethylated sites differentially methylated between leukemic and control samples.

<p>Distribution of hyper- and hypomethylated sites differentially methylated between leukemic and control samples.</p

Top ten KEGG pathways connected with genes containing sites differentially methylated between specific genetic subtype and remaining BCP ALL patients.

<p>Top ten KEGG pathways connected with genes containing sites differentially methylated between specific genetic subtype and remaining BCP ALL patients.</p

PCA based on 118,871 sites differentially methylated between BCP ALL and control samples.

<p>PCA based on 118,871 sites differentially methylated between BCP ALL and control samples.</p

PCA based on filtered probes set minimizing the variation of methylation profiles in leukemic samples.

<p>PCA based on filtered probes set minimizing the variation of methylation profiles in leukemic samples.</p

Selected disease phenotypes enriched by genes associated with uniform leukemia methylation pattern.

<p>Selected disease phenotypes enriched by genes associated with uniform leukemia methylation pattern.</p